Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB), kills more than 2 million people worldwide annually. M.bovis BCG, the only TB vaccine available, is of limited efficacy. The emergence of effectively untreatable extremely drug resistant (XDR) and multi-drug resistant (MDR) strains of Mtb underscores the requirement for an effective TB vaccine. Despite identification of several promising Mtb antigen vaccine candidates, our poor understanding of the requirements of early and effective memory responses to Mtb remains a significant challenge to the development of effective vaccine strategies. Interferon-gamma (IFN )-producing T helper 1(Th1) memory cells are required for effective protection against TB. However, we recently reported that an Interleukin (IL)-17-producing CD4+ T helper (Th17) memory cells are required for accumulation of Th1 memory cells and protective memory responses to Mtb challenge. We hypothesize that successful vaccination against TB requires Th17 memory cells. According to this hypothesis, vaccination with Mtb antigen results in the generation of antigen specific-Th17 and Th1 CD4+ cells, the Th17 cells being sequestered in the lung. Upon subsequent challenge with Mtb, lung resident Th17 memory cells proliferate rapidly, producing IL-17 and triggering the local expression of chemokines. We will test this hypothesis in three aims.
Aim 1 : Identifying the specific factors required for effective Th17 memory response following Mtb challenge.
Aim 2 : The mechanism by which Th17 memory cells mediate Th1 accumulation.
Aim 3 : To determine whether increasing the Th17 lung resident population improves vaccine- induced protection against TB. The work proposed in this grant will significantly impact the design of future vaccine strategies by allowing us to target IL-17 with the long-term goal of improving vaccine strategies against TB in humans.

Public Health Relevance

Tuberculosis(TB), caused by the organism M.tuberculosis (Mtb) kills more than 2 million people worldwide every year. To improve immunization strategies against TB, it important for us to understand the basic requirements for induction of long-lived effective immunity in the lung against TB. The relevance of this work to public health is that it will significantly impact the design of future vaccine strategies by allowing us to improve vaccine-induced Th17 responses to generate better vaccine-induced immunity against TB will therefore have the potential to reduce the incidence of TB.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL105427-04
Application #
8740775
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Peavy, Hannah H
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$342,000
Indirect Cost
$117,000
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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